Twenty-one double-blind RCTs were included with a total of 7245 participants. All except one of the studies used an intention to treat last observation carried forward analysis.
1. Global efficacy:
All new antipsychotics and haloperidol reduced the BPRS global score more effectively than placebo.
Pooled mean BPRS changes were (all results were significant but 95% CI not reported):
Olanzapine vs placebo r=0.23 (n=574 participants, 2 studies).
Quetiapine vs placebo r=0.23 (n=991 participants, 4 studies).
Risperidone vs placebo r=0.28 (n=686 participants, 2 studies).
Sertindole vs placebo r=0.20 (n=649 participants, 2 studies).
Haloperidol vs placebo r=0.28 (n=814 participants, 5 studies).
All antipsychotics vs placebo r=0.25, 95% CI: 0.22, 0.28.
Risperidone and olanzapine produced statistically significant but modest effects that were superior to haloperidol, but the olanzapine studies showed significant heterogeneity.
Pooled mean BPRS changes were (95% CI not reported):
Olanzapine vs haloperidol r=0.07, statistically significant, but significant heterogeneity chi-squared=9.84, p<0.01 (n=2994 participants, 3 studies).
Quetiapine vs haloperidol r=-0.05 (n=953 participants, 2 studies).
Risperidone vs haloperidol r=0.06, statistically significant (n=2926 participants, 2 studies).
Sertindole vs haloperidol r=-0.03 (n=1218 participants, 1 study).
The heterogeneity for olanzapine disappeared in the sensitivity analysis of optimum doses (see 'Sensitivity analysis after exclusion of subtherapeutic and supratherapeutic doses').
2. Negative symptoms:
All antipsychotics (atypicals and haloperidol) induced significantly higher reductions from baseline to end point than placebo.
Pooled mean changes in negative symptoms were (all results were significant but 95% CI not reported):
Olanzapine vs placebo r=0.21 (n=582 participants, 2 studies).
Quetiapine vs placebo r=0.19 (n=823 participants, 4 studies).
Risperidone vs placebo r=0.20 (n=686 participants, 2 studies).
Sertindole vs placebo r=0.21 (n=392 participants, 1 study).
Haloperidol vs placebo r=0.17 (n=796 participants, 5 studies).
Olanzapine and risperidone were both superior to haloperidol whereas sertindole and haloperidol were equally effective.
Pooled mean changes in negative symptoms were (95% CI not reported):
Olanzapine vs haloperidol r=0.08, statistically significant (n=2993 participants, 3 studies).
Quetiapine vs haloperidol r=-0.12, statistically significant (n=487 participants, 2 studies).
Risperidone vs haloperidol r=0.04, statistically significant (n=3000 participants, 5 studies).
Sertindole vs haloperidol r=-0.01 (n=1125 participants, 1 study).
3. Use of antiparkinson medication:
All four new antipsychotics were associated with a similar use of antiparkinson medication as placebo and all were clearly superior to haloperidol in this respect.
The use of antiparkinson medication (95% CI not reported):
Olanzapine vs placebo r=-0.02 (n=418 participants, 2 studies).
Quetiapine vs placebo r=0.06 (n=716 participants, 4 studies).
Risperidone vs placebo r=-0.09, 95% CI: -0.18, 0.00 (n=436 participants, 2 studies).
Sertindole vs placebo r=0.07 (n=494 participants, 2 studies).
Haloperidol vs placebo r=-0.36 statistically significant, p<0.05 (n=696 participants, 5 studies).
The use of antiparkinson medication (all statistically significant, but 95% CI not reported):
Olanzapine vs haloperidol r=0.35, but significant heterogeneity chi-squared=5.46, p<0.05 (n=2694 participants, 3 studies).
Quetiapine vs haloperidol r=0.38 (n=758 participants, 2 studies).
Risperidone vs haloperidol r=0.12, 95% CI: 0.07, 0.16, p<0.000001 (n=1938 participants, 5 studies).
Sertindole vs haloperidol r=0.34 (n=424 participants, 1 study).
The heterogeneity for olanzapine disappeared in the sensitivity analysis of optimum doses (see 'Sensitivity analysis after exclusion of subtherapeutic and supratherapeutic doses'). Three studies chose comparators other than haloperidol (risperidone vs zuclopenthixol; risperidone vs perphenazine; quetiapine vs chlorpromazine). In the latter two studies conventional antipsychotics were not associated with statistically significantly greater use of anitparkinson medication than their newer counterparts (p=0.54 and 0.27 respectively).
4. Analysis of dropout rates:
Only the smaller of the sertindole studies provided exact drop-out rates. With the exception of sertindole all antipsychotics showed fewer drop-outs than placebo due to the lack of efficacy of the placebo. No antipsychotic had any significantly different number of drop-outs due to adverse events compared to placebo.
Olanzapine vs placebo r=0.00, 95% CI: -0.09, 0.10, p>0.5.
Quetiapine vs placebo r=0.02, 95% CI: -0.06, 0.09, p>0.5.
Risperidone vs placebo r=0.03, 95% CI: -0.15, 0.21, p>0.5.
Sertindole vs placebo r=-0.01, 95% CI: -0.15, 0.13, p>0.5.
Haloperidol vs placebo r=-0.02, 95% CI: -0.13, 0.10, p>0.5.
Only the following were found to be statistically significant for comparisons with haloperidol:
Olanzapine vs haloperidol. Drop-outs due to treatment failure r=0.09, 95% CI: 0.05, 0.13, p<00001.
Drop-outs due to adverse events r=0.06, 95% CI: 0.02, 0.10, p<0.005.
Quetiapine vs haloperidol.
Drop-outs due to adverse events r=0.17, 95% CI: 0.10, 0.24, p<00001.
5. Sensitivity analysis after exclusion of subtherapeutic and supratherapeutic doses:
Several of the studies were designed as dose finding studies for new compounds and so a sensitivity analysis was conducted to exclude doses now thought to be subtherapeutic or supratherapeutic. The sensitivity analyses did not change the overall results, but quetiapine was no longer statistically significantly inferior to haloperidol in the treatment of negative symptoms and risperidone showed a tendency to be more effective and to be associated with less EPS.